Table 2.

Top drugs identified using enrichment analysis

Drug name	Indication	Smoking trait	Minimal P value and tissue typesa	MAGMAb	Referencec
Putative drug targets that may be repurposed for smoking cessation
Dextromethorphan	Coughing	CigDay	3.3 × 10−39 (caudate basal ganglia)	1.0 × 10−4	32,41
		SmkInit	9.2 × 10−15 (brain spinal cord cervical C1)	0.36
		SmkCes	2.8 × 10−4 (brain spinal cord cervical C1)	9.2 × 10−9
Ganaxolone	Seizure disorders (investigated)	CigDay	1.3 × 10−9 (substantia nigra)	0.05	33
		SmkInit	3.5 × 10−3 (cerebellum)	0.66
		SmkCes	0.08 (caudate basal ganglia)	0.02
Galantamine	Alzheimer’s disease	CigDay	4.2 × 10−73 (substantia nigra)	7.7 × 10−14	34,42
		SmkInit	1.3 × 10−4 (brain spinal cord cervical C1)	4.3 × 10−3
		SmkCes	0.020 (cortex)	3.4 × 10−9
Clinical drugs identified
Nicotine	Smoking cessation	CigDay	4.2 × 10−71 (substantia nigra)	4.3 × 10−17	First-line therapy
		SmkInit	1.3 × 10−5 (hypothalamus)	0.01
		SmkCes	0.03 (amygdala)	5.8 × 10−11
Varenicline		CigDay	4.8 × 10−26 (frontal cortex BA9)	5.6 × 10−6	First-line therapy
		SmkInit	9.2 × 10−15 (brain spinal cord cervical C1)	5.9 × 10−3
		SmkCes	2.8×10−4 (brain spinal cord cervical C1)	8.2 × 10−9
Bupropion		CigDay	9.0 × 10−19 (brain spinal cord cervical C1)	0.62	First-line therapy
		SmkInit	9.2 × 10−15 (brain spinal cord cervical C1)	0.92
		SmkCes	2.8 × 10−4 (brain spinal cord cervical C1)	0.05
Cytisine		CigDay	3.9 × 10−132 (frontal cortex BA9)	5.6 × 10−6	Second-line therapy
		SmkInit	9.2 × 10−15 (brain spinal cord cervical C1)	5.9 × 10−3
		SmkCes	2.8 × 10−4 (brain spinal cord cervical C1)	8.2 × 10−9
Anxiolytic drugs (butalbital)d		CigDay	4.8 × 10−132 (frontal cortex BA9)	1.1 × 10−3	Second-line therapy
		SmkInit	4.9 × 10−5 (cerebellar hemisphere)	7.3 × 10−3
		SmkCes	1.1 × 10−3 (caudate basal ganglia)	0.33

Drug enrichment analysis of TESLA results implicates drugs with biological relevance and drugs that are being clinically evaluated. We created gene sets of drug target genes and tested whether these gene sets were enriched with TESLA hits. The most significant TESLA P values for enrichment analysis are shown and, as a comparison and validation, we also show enrichment analysis based on MAGMA for implicated drugs. Full results are available in Supplementary Table 14. All P values are two sided.

^aThe minimal P value in 13 brain tissues; significance Bonferroni’s corrected P values that are under 5% threshold and labeled bold.

^bMAGMA using the GWAS signals; significant P values after Bonferroni’s correction are labeled bold.

^cReferences where the candidate drugs were discussed.

Preliminary clinical/basic evidence/references support the drug repositioning.

^dComplete enrichment results for anxiolytic drugs are shown in Supplementary Table 14.